DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies

Pechalrieu, Dany; Etiévant, Chantal; Arimondo, Paola B.

doi:10.1016/j.bcp.2016.12.004

Cited by 91 publications

(60 citation statements)

References 139 publications

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“…[27,31,52,53] By generating atotal of six dAC and ribonucleotide versions,w eh ave uncovered information on efficient synthesis and on how the photocagesattachment site influences photolysis yield. Areas of interest include regenerative medicine, [55] developmental biology, [4] development and progression of cancer, [56] and the development of therapeutic routes [18,38,[57][58][59] to treat surface-accessible tissues. [54] Finally,d AC and related drugs could be modified with photoswitches that regulate bioactivity through photo-isomerable conformation changes rather than photolysis.…”

Section: Angewandte Chemiementioning

confidence: 99%

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

et al. 2019

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Controlling the functional dynamics of DNAwithin living cells is essential in biomedical research. Epigenetic modifications such as DNAmethylation play akey role in this endeavour.D NA methylation can be controlled by genetic means.Y et there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present as mall-molecule approach to modulate DNAm ethylation with light. The strategy uses aphoto-tuneable version of ac linically used drug (5-aza-2'-deoxycytidine) to alter the catalytic activity of DNAmethyltransferases,the enzymes that methylate DNA. After uptake by cells,t he photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells.T he chemical tool complements genetic,b iochemical, and pharmacological approaches to study the role of DNAm ethylation in biology and medicine.The methylation of DNAatposition 5ofcytosine residues is chemically av ery simple but biologically one of the most important modifications of DNA. It influences many biological processes in humans such as the regulation of cell function, cellular reprogramming,a nd organismal development. [1][2][3][4][5][6][7] Biological effects of higher methylation levels at promoters are mediated by lowering the transcription of genes either by blocking the binding of transcription factors or by recruiting unique methyl-recognizing proteins that lower gene expression. Altered levels of methylation are also associated with several diseases [8][9][10][11] including cancer. [8,[12][13][14][15][16] Driven by the growing importance of DNAmethylation in biomedical research, there is as trong interest to experimentally lower or increase methylation levels [17][18][19][20][21][22][23] to study,f or example,t he role of epigenetic reprogramming in tissue development or regenerative medicine. [24,25] Optical control is of particular relevance given the high spatial and temporal resolution of light. Often, the approach is implemented with photosensitive small molecules of tuneable bioactivity. [26][27][28][29][30][31] These can be used without the need for genetic engineering of cells leading to powerful applications within cell biology. [32] Yet, despite the importance of DNAm ethylation in biology, no light-tuneable small-molecule tool has been developed to manipulate methylation levels in cells.Herein, we present ap hoto-mediated small-molecule strategy that modulates methylation in light-exposed cells. At the approachsc entre is an inhibitor that interferes with DNAmethyltransferases (DNMTs), the enzymes responsible for DNAm ethylation [33] including the maintenance DNA methyltransferase 1( DNMT1). [34] Thei nhibitorsb ioactivity becomes tuneable with light by the chemical derivatization with ap hotocage.A ss chematically illustrated in Figure 1a, the attached photocage renders the inhibitor biologically inactive.However, light exposure cleaves off the photocage to restore the original inhibitory effect (Figure 1a). Thep hotocaged molecule is hence expected...

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Section: Angewandte Chemiementioning

confidence: 99%

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

et al. 2019

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“…Although epigenetic modification does not lead to DNA sequence variation, it results in interplay between genes and phenotype . Aberrant patterns of DNA methylation have been suggested in many malignancies . The relationship between patterns of DNA methylation and tumorigenesis comes back in 1983, when investigators described a decreased level of DNA methylation in human colon cancer .…”

Section: Dna Methylation and Tumorigenesismentioning

confidence: 99%

“…It is accurate that both hypermethylation and hypomethylation contribute to tumorigenesis process. Global hypomethylation, stimulating DNA instability, and hypermethylation of CpG islands on tumor suppressor gene (TSG) promoters lead to gene inactivation . Human viruses causing tumorigenesis can alter expression of DNMTs (Figure ); however, it does not contain particular trend …”

Section: Dna Methylation and Tumorigenesismentioning

confidence: 99%

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DNA methyltransferases in virus‐associated cancers

Charostad

Astani

Goudarzi

et al. 2018

Reviews in Medical Virology

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Summary Human tumor viruses are either casually linked or contribute in the development of human cancers. Viruses can stimulate oncogenesis through affecting diverse biological pathways in human cells. Growing data have demonstrated frequent involvement of one of the most characteristic parts of cellular epigenetic machinery, DNA methylation, in the oncogenesis. DNA methylation of cellular genes is catalyzed by DNA methyltransferases (DNMTs) as a key effector enzyme in this process. Dysregulation of DNMTs can cause aberrant gene methylation in promoter of cancer‐related genes including tumor suppressor genes, resulting in gene silencing. In this regard, the role of tumor viruses is remarkable. Here, in this review, we used published information to elucidate whether tumor viruses are able to manipulate DNMT regulation, and if so, what are its consequences in the process of oncogenesis. This essay also aims to shed light on which cellular pathways have been engaged by viruses to induce DNMTs.

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“…For instance, the DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) catalyze the methylation of the 5-position of cytosine residues in DNA [7], while DNA demethylases (TET1, TET2, and TET3) catalyze the removal of methyl group [8]. The histone tail modifications are much more diverse and therefore are catalyzed by a long list of enzymes.…”

Section: Introductionmentioning

confidence: 99%

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Young

Chang

2017

MOJBB

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Cancer is associated with epigenetic changes such as abnormal DNA methylation and histone tail modifications, and these changes result in tumor suppressor gene silencing, oncogene overexpression, and genome instability -phenomena that are closely linked to cancer development. The epigenetic marks on DNA and histones are reversible and therefore it is possible to restore normal patterns through chemically targeting epigenetic regulators that generate, maintain, recognize, and remove these marks. In recent years, fragment-based drug discovery (FBDD) has been used to target both the protein-protein interactions (PPI) as well as the enzymatic functions of epigenetic factors. Low molecular weight fragments (MW<300) efficiently sample chemical space and can bind to discreet binding pockets on target proteins such as those found on PPI interface. In this review, we describe the biophysical, biochemical, and in silico methods used for FBDD. We also discuss the examples of using FBDD to target epigenetic readers such as bromodomain-containing proteins and epigenetic enzymes such as arginine methyltransferases 6 (PRMT6), lysine demethylase 4 (KDM4), and Sirtuin 2 (SIRT2). FBDD provides an economical alternative to traditional high throughput screening. Effective FBDD endeavors depend heavily on gaining structural information of ligand-protein interactions early on and the close collaboration between biophysicists, chemists, and biologists in all stages of the drug discovery process. Using FBDD, protein-protein interactions in non-enzymatic epigenetic factors can potentially be chemically modulated. Furthermore, FBDD enables the identification of new binding pockets that can improve compound specificity against various epigenetic enzymes.

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DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies

Cited by 91 publications

References 139 publications

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

DNA methyltransferases in virus‐associated cancers

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

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